Allosteric Regulation of MKP-1 in Liver Metabolism

About This Grant

PROJECT SUMMARY Mitogen-activated protein kinase phosphatase-1 (MKP-1) is a nuclear localized dual specificity phosphatase that dephosphorylates the regulatory tyrosine and threonine residues in the activation loop of MAPKs. MKP-1 preferentially dephosphorylates the nuclear pool of JNK1/2 and p38 MAPK and is found to play significant regulatory roles in metabolism. It is found to be upregulated in the liver of mice fed a high fat diet (HFD) and in obese human. Given the significant increase in liver disease as a result of obesity, understanding the mechanisms of aberrant MKP-1 signaling on liver metabolism is important. This is supported by liver-specific deletion of MKP-1 (MKP-1 LKO), which protects against hepatic steatosis. These observations raise the exciting possibility that MKP-1 can be targeted for the treatment of metabolic associated steatotic dysfunction liver disease (MASLD). Although MKP-1 represents an attractive target for pharmacological inhibition it has been considered largely ‘undruggable’ partly due to the high similarity between PTP active sites and the propensity for active site compound selection, which often leads to charged compounds hits with poor bioavailability. Our lab has recently developed specific allosteric inhibitors for MKP-5. These inhibitors bind to a previously undescribed allosteric site within the catalytic domain. Mutation of the allosteric site dramatically inhibits MKP-5 catalysis and serves as a docking site for MAPK. This site is highly conserved amongst all active MKPs, including MKP-1, suggesting that it has an essential conserved role for catalysis. Therefore, I hypothesize that the MKP-1 allosteric site is critical for the regulation of its catalytic activity and binding to MAPKs, and that this site represents a target for the development of allosteric small molecule inhibitors for the treatment of MASLD.